Anh Duc Pham(1)*, Maria Sanz-Codina(2)* , Bernhard Rössler(3), Christian Zauner(4), Eva Schaden(3), Gottfried Heinz(3), Thomas Staudinger(5), Philip Nasztl(2), Theresa Pecho(2), Maria Weber(2), Christoph Dorn(6), J.G. Coen van Hasselt(1), Markus Zeitlinger(2)
(1). Leiden Academic Centre for Drug Research, Leiden University - Leiden (The Netherlands) (2). Department of Clinical Pharmacology, Medical University of Vienna - Vienna (Austria) (3) .Department of Anesthesia, Intensive Care Medicine and Pain Medicine, Medical University of Vienna - Vienna (Austria) (4). Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna - Vienna (Austria) (5) .Department of Medicine I, ICU 13.i2, Medical University of Vienna - Vienna (Austria) (6). Institute of Pharmacy, University of Regensburg - Regensburg (Germany) (*)Equal contribution
Background:
Linezolid, an antimicrobial drug, is commonly used to treat bacterial pneumonia and skin and soft tissue structure infections (SSTIs) associated with MRSA, serving as an alternative to vancomycin [1]. However, the selection of antibiotic therapy for critically ill sepsis patients, particularly in terms of target site penetration of linezolid, is a complex task due to the physiological changes that alter drug pharmacokinetics (PK). Therefore, the objective of this study was to investigate the impact of sepsis-associated inflammation on the target site penetration of linezolid in subcutaneous adipose tissue, by developing a population PK model based on plasma and subcutaneous adipose tissue PK data from healthy volunteers and septic patients.
Methods:
Study data: In this study, 10 septic patients (42-86 years, 24.2-34.5 kg/m2) and 2 healthy volunteers (29-33 years, 22.6-25.9 kg/m2) were administered linezolid as single and multiple intravenous doses (600 or 1200 mg, infused over 30 minutes). Total and free drug concentrations were measured in plasma and subcutaneous tissue over 8 hours after the last dose. Plasma samples were taken at pre-dose, 0.5, 1, 2, 4, 6 and 8 hours post-dose. Free plasma concentrations were measured after ultrafiltration. Free subcutaneous tissue concentrations were determined by microdialysis (MD) at 1 h hour intervals and corrected using retrodialysis (RD), determined for each individual. Linezolid concentrations were analysed using high-performance liquid chromatography with ultraviolet detection (HPLC-UV). Model development was performed using 249 concentration observations from the 12 participants.
Model development: A population PK model was developed to describe the PK of linezolid in plasma and subcutaneous adipose tissue. The unbound fraction was estimated based on the determined total and free concentrations. One-, two- and three-compartment models with first-order elimination were evaluated to describe plasma concentrations. Recovery-corrected MD data were modelled using an established approach integrating the tissue concentration-time curve at each sampling interval [2]. Differences between healthy subjects and septic patients were investigated for all parameters. Inter-individual variability (IIV) was assessed for all structural model parameters and included using an exponential mode. Data were modelled in NONMEM® 7.4 with FOCE. The probability of target attainment (PTA) was determined using Monte Carlo simulations with a target of fAUC24h/MIC≥ 100 [3], based on simulations of of either 600 mg q12h or 12 600 mg q12h i.v over 30 minutes linezolid infusion.
Results:
The plasma PK was best described by a 2-compartment model with IIV estimated for clearance (CL) and central distribution volume (Vc). Subcutaneous adipose concentrations were described by concentrations in the peripheral compartment (Vp). Additional separate compartments for tissue data led to instability and estimation issues. A scaling factor of tissue concentrations showed no significant improvement in model fit. Goodness-of-fit plots and VPCs indicated overall adequate model performance. Estimated separated parameters such as CL, Vc, Q and Vp for healthy volunteers and septic patients showed no significant improvement or high uncertainty parameters. The respective final estimated values [RSE%] are 7.35 L/h [19.2], 31 L [14.9], 39.2 L/h [16.7], 30.7 L [17.2]. The only significant difference identified between healthy and septic patients was regarding protein binding, which was 0.958 [3.1] in septic patients and 0.725[6.2] in healthy volunters. Linezolid plasma concentrations were within the clinical range [4]. For both septic patients and healthy volunteers, a PTA of ≥90% was achieved for MIC values up to 2 mg/L after a 600 mg q12h dose and up to 4 mg/L after a 1200 mg q12h dose in plasma and subcutis.
Conclusion:
The developed population PK model was able to characterize the linezolid plasma and subcutis PK profile. Plasma PK parameters are comparable with previous reports [5]. No relevant differences in PK parameters, except for PB, were found between septic patients and healthy volunteers. The limited healthy volunteer sample size could explain this. Further research and data are needed to better evaluate the differences between healthy and sepsis patients beyond this exploratory analysis. A linezolid dose of 600 mg twice daily of linezolid seems to be sufficient to treat SSTIs caused by most relevant pathogens.
References
[1] S. M. R. Hashemian, T. Farhadi, M. Ganjparvar, Drug Des Devel Ther 2018, 12, 1759.
[2] K. Tunblad, M. Hammarlund-Udenaes, E. N. Jonsson, Pharm Res 2004, 21, 1698.
[3] I. K. Minichmayr, A. Schaeftlein, J. L. Kuti, M. Zeitlinger, C. Kloft, Clin Pharmacokinet 2017, 56, 617.
[4] G. A. Richards, A. J. Brink, Crit Care 2014, 18, 525.
[5] E. Bandín-Vilar, L. García-Quintanilla, A. Castro-Balado, I. Zarra-Ferro, M. González-Barcia, M. Campos-Toimil, V. Mangas-Sanjuan, C. Mondelo-García, A. Fernández-Ferreiro, Clin Pharmacokinet 2022, 61, 789.
Reference: PAGE 32 (2024) Abstr 11189 [www.page-meeting.org/?abstract=11189]
Poster: Drug/Disease Modelling - Infection